Environmental factors in causing human cancers: emphasis on tumorigenesis
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- Sankpal, U.T., Pius, H., Khan, M. et al. Tumor Biol. (2012) 33: 1265. doi:10.1007/s13277-012-0413-4
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The environment and dietary factors play an essential role in the etiology of cancer. Environmental component is implicated in ~80 % of all cancers; however, the causes for certain cancers are still unknown. The potential players associated with various cancers include chemicals, heavy metals, diet, radiation, and smoking. Lifestyle habits such as smoking and alcohol consumption, exposure to certain chemicals (e.g., polycyclic aromatic hydrocarbons, organochlorines), metals and pesticides also pose risk in causing human cancers. Several studies indicated a strong association of lung cancer with the exposure to tobacco products and asbestos. The contribution of excessive sunlight, radiation, occupational exposure (e.g., painting, coal, and certain metals) is also well established in cancer. Smoking, excessive alcohol intake, consumption of an unhealthy diet, and lack of physical activity can act as risk factors for cancer and also impact the prognosis. Even though the environmental disposition is linked to cancer, the level and duration of carcinogen-exposure and associated cellular and biochemical aspects determine the actual risk. Modulations in metabolism and DNA adduct formation are considered central mechanisms in environmental carcinogenesis. This review describes the major environmental contributors in causing cancer with an emphasis on molecular aspects associated with environmental disposition in carcinogenesis.
KeywordsEnvironmental factorsCarcinogenesisNicotinePolycyclic aromatic hydrocarbons
Cancer is one of the major causes of human deaths in the world. According to the American Cancer Society, cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries. The World Health Organization (WHO) reported that cancer accounted for 7.6 million deaths in the year 2008. Based on the current projections, the number of worldwide cancer deaths is expected to increase to 11.4 million by 2030 . The precise causes of cancer are still not known. It is expected that both external and internal factors contribute to several cancers. The internal factors include gene mutations, changes in hormonal and immune systems, and metabolic abnormalities. Environmental elements that interact with humans account for having a correlation with at least two thirds of cancer cases in the United States. These factors include lifestyle choices like excessive alcohol consumption, unhealthy diet, exposure to excessive sunlight and carcinogenic chemicals, lack of exercise, and cigarette smoking. The lifestyle choices one chooses to indulge in, along with the environmental factors one is exposed to, are linked to the development of specific types of cancer. For example, alcohol consumption is linked primarily to liver cancer while smoking is a major contributor for lung, oral, and gastric cancers.
Lifestyle habits such as tobacco use and alcohol consumption work as contributing factors to the development of cancer. Tobacco is processed from plants of the genus Nicotiana and it is consumed commonly in the forms of smoking, chewing, and snuffing. Cigarettes, cigars, and pipe tobacco are made from dried tobacco leaves. Nicotine is the major constituent in tobacco but there are more than 60 chemicals in tobacco that are known to cause cancer, including ammonia, tar, and carbon monoxide. According to Centers for Disease Control and Prevention (CDC), 46 million adults in the United States were current smokers in 2008 and tobacco is responsible for about 1 in 5 deaths in the United States. In the United States alone, the estimated productivity loss due to tobacco use is $97 billion annually, and tobacco-related health care costs around $96 billion per year .
The addictive ingredient in tobacco is nicotine and its stimulant properties contribute to the regular use of tobacco products and further lead to addiction in majority of users. Tobacco use is linked to several malignancies, including lung, gastric, bladder, and oral cancers. Cigarettes are believed to have more than 15 known carcinogens including polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, and aromatic amines , while chewing tobacco and snuff are believed to have 28 carcinogens. The mechanisms associated with tobacco and cancer is primarily attributed to the mutagenic response of carcinogens and the antiapoptotic mechanisms of nicotine. Nicotine actually lacks mutagenic properties but inhibits programmed cell death (apoptosis) and therefore plays an active role in tumor formation. Nicotine acts as a tumor-promoting agent by increasing total protein kinase C (PKC) activity thereby suppressing apoptosis. PKC activity deprives granulocyte-macrophage colony-stimulating factor and interleukin 3, which are both important factors involved in cell death . Nicotine derivatives such as nicotine-derived nitrosamine ketone (NNK) is a potent procarcinogen and will act as a carcinogen when activated through cytochrome P450 (CYP) family enzyme CYP2A6 .
Smoking causes many health hazards including cancer, heart disease, aneurysms, bronchitis, emphysema, and stroke. Smoking is majorly associated with lung cancer and smokeless tobacco (chewing tobacco or snuff) more commonly associated with oral cancer. The environment and genetic factors are involved in the onset of lung cancer [6, 7]; however, there is a strong association of environment with this malignancy. Lung cancer is the leading cause of cancer-related deaths in the world and it is responsible for one-third of deaths among cancer patients in the United States [8, 9]. The prognosis of this malignancy is very poor and 5-year relative survival rates are approximately 13 % for men and 17 % for women . According to the American Cancer Society (ACS), smoking is responsible for at least 30 % of cancer related deaths. Lung cancer is one of the complicated malignancies to treat.
Cigarette smoke contains nicotine and derivatives  that are major risk factors in the development of lung cancer . Cigarette smoking-related lung cancer is responsible for 90 % of cases in men and 79 % in women in the United States . Smoking is a negative prognostic factor and possesses a direct biological effect on the survival of lung cancer patients [14–16]. It can also cause or modulate the relapse of early stage non-small cell lung cancer (NSCLC) after treatment . Patients diagnosed with tobacco-related cancers possess a higher risk for developing a second malignancy due to field carcinogenesis effects [18, 19] and continued smoking during therapy causes lower response to chemotherapy and/or radiation therapy [20–22].
Smokeless tobacco products have a role in the onset of throat, mouth, esophageal stomach, and pancreatic cancers. Chewable tobacco is a type of smokeless tobacco and its users chew tobacco loose leaves and spit out the tobacco juices. Nicotine is absorbed through the buccal mucosa and carried in the bloodstream to other areas of body, including the brain. Nicotine's effects on the central nervous system are critical in the development of addictive behaviors and furthermore, ingestion of large quantities of tobacco contribute to cancer. In comparison, users who chew tobacco receive a larger dose of nicotine than cigarette smokers. However, just as the case with cigarettes, chewable forms of tobacco are filled with at least 28 carcinogens including PAHs, of which nitrosamines are the most carcinogenic.
Carcinogens are agents directly involved in causing cancer. They can be substances or factors in the environment. The International Agency for Research on Cancer (IARC) of WHO found and classified close to 100 compounds as being carcinogenic to humans through evaluation of about 1,000 possible cancer-causing candidates.
Dioxins are regarded as highly toxic compounds that play a significant role in environmental pollution. They are a class of polyhalogenated compounds which include polychlorinated dibenzodioxins, polychlorinated dibenzofuran, and polychlorinated biphenyls. They are produced as a result of combustion of organic substances in contact with chlorine, halogenated plastics (PVC), and pesticides (i.e., hexachlorobenzene). Environmental dioxins are largely produced during waste incineration, pulp and paper manufacturing, and other industrial processes. Household exposure is primarily from dietary fat, particularly milk, fish, and other meat products . Occupational exposure occurs during the production of phenoxy herbicides and chlorophenols.
In vitro and in vivo studies of the reference chemical for mixtures of dioxins and furans, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has shown to have endocrine disrupting properties. TCDD is classified as a class I human carcinogen [37, 38] that has been implicated in fibrosarcomas, lymphomas, and neoplasms . Animals treated with TCDD  developed tumors of the liver, lung, skin, thyroid, oral cavity as well as other sites.
Dioxins including TCDD are environmentally and biologically stable with an estimated half-life of 7.6 years in humans, leading to chronic exposures . After exposure, TCDD primarily accumulates in the hepatic and adipose tissues due to its lipophilic nature. Since it is classified as an endocrine system disruptor, chronic low level exposures to TCDD could have implications in hormonally dependent cancers such as breast cancer . Several studies have also shown that there is an increased risk of sarcoma and lymphoma in people exposed to dioxin emissions from incinerators [43, 44].
TCDD is a non-mutagenic and non-genotoxic carcinogen. It is often distinguished as being a potent promoter and a weak initiator. TCDD or its metabolites do not directly bind DNA but rather exert its carcinogenic effect by altering signal transduction pathways and cell replication, and by indirect oxidative damage of DNA which often leads to tumor promotion . Mechanistic studies have shown that the toxic effects of TCDD are brought about by its binding to the aryl hydrocarbon receptor (AhR) and subsequent activation of a variety of genes . The AhR binds to a variety of ligands and the cytosolic AhR is bound by heat shock proteins (HSP90), small protein (p23), and an immunophilin-like protein (XAP2) [46, 47]. Binding of ligand TCDD to AhR causes it to dissociate from the complex of proteins. The TCDD-bound receptor then translocates to the nucleus where it forms a heterodimer with aryl hydrocarbon receptor nuclear translocator (Arnt) proteins. The AhR-Arnt heterodimer acts as a transcription factor and modulates genes expression by binding to the dioxin responsive elements present in 5′ promoter regions of Ah-responsive genes including CYP1A1, glutathione S-transferase, and glucuronyl transferase. The activation of CYP1A1 by chemicals that bind AhR including TCDD is often used as a biomarker in epidemiological studies . The exact mechanisms are currently unknown; however, the majority of the observed toxic effects of TCDD are thought to be mediated through AhR.
Chlorinated drinking water is particularly dangerous because it contains a complex mixture of chlorinated and brominated by-products, in particular trichloromethane, with mutagenic and carcinogenic activities [49, 50]. Long-term consumption of chlorinated water has shown to increase the risk of adult leukemia, colorectal cancer, and bladder cancer [51–54].
Polycyclic aromatic hydrocarbons
Polycyclic aromatic hydrocarbons (PAH) refer to a class of lipophilic chemicals that consist of fused aromatic rings. PAHs are potent environmental pollutants that are derived mainly from the incomplete combustion of organic material like coal, wood, gasoline, garbage, and tobacco. They are also formed during certain industrial processes like aluminum production, coal gasification, iron and steel foundries, and carbon electrode production. Dietary sources of PAH include smoked and grilled foods and foods that are contaminated by ambient air pollution. The major sources of exposure in the general population are tobacco smoking  along with diet and exposure to fossil fuel combustion by-products .
PAH exposure has been linked to skin, bladder, and lung cancer in humans through vigorous evidence [57, 58]. Also, tobacco smoking, occupational exposures, and smoked meats have all been linked to PAH exposure [59–61]. PAHs are metabolized by xenobiotic-metabolizing enzymes to form phenols and oxides. PAHs can be activated either by cytochrome P450 (CYP1A1 or CYP1B1), microsomal epoxide hydrolase, or by aldo-keto reductase to form PAH diol-epoxides or PAH o-quinones, respectively. These reaction intermediates react with DNA to form stable and depurinating adducts that induce mutation(s), predominantly in the form of guanine to thymine transversions (Fig. 2) [62–64]. The formation of these PAH-DNA adducts is a crucial event in the initiation of carcinogenesis [65–67]. Before a PAH-diol-epoxide metabolite can adduct DNA, these intermediate products may be further metabolized by phase II enzymes (glutathione S-transferase (GST) family) to more polar products that can be excreted by the body . A key determinant to an individual's risk for cancer can be the inherited genetic differences in the expression of these metabolizing enzymes and the body's ability to metabolize PAH [69–71].
The International Agency for Research on Cancer (IARC) has classified PAH mixtures as carcinogens to humans and has identified individual PAHs as possible human carcinogens [72, 73]. PAHs can associate with fine carbon particles suspended in air and these particles accumulate near ground level, thus allowing extensive penetration of organisms. A study conducted by the American Cancer Society reported that higher concentrations of fine particles in the air corresponded with increased deaths due to lung cancer, and smoking was found to potentiate this effect . Results from prospective studies suggest that exposure to air pollution (particulate PAH) increases the risk of lung cancer by up to 8 % [74, 75].
Volatile organic compounds
Volatile organic compounds (VOC) are associated with a variety of long-term health risks since they are representative of an important group of indoor and outdoor pollutants . VOCs are comprised of compounds like benzene, formaldehyde, styrene, and chlorinated hydrocarbons like trichloroethylene, tetrachloroethylene, carbon tetrachloride, and chloroform. Although the majority of health issues related to VOC are due to occupational exposure, there is a growing concern about VOC exposure indoors. Some VOCs may be present at considerably low concentrations, but they still may pose a risk due to chronic exposure. Some of the daily used products that contain VOCs include inks, paints, and glues (toluene, xylene, n-hexane, vinylchloride); stain removers (carbon tetrachloride, trichloroethane, tetrachloroethylene); household cleaning products (chloroform, ethanol, phenol, dimethylammoniochloride); cosmetics (ethylacetate, acetone, phenolic compounds); and wood preserving products (pentachlorophenol, p-dichlorobenzene). Concentrations of pollutants indoor are usually higher than those encountered outdoors and since people spend up to 80 % of time indoors (home, office, public buildings); it is a major contributor to personal exposure [77, 78].
The indoor/outdoor ratio is often used to assess the influence of outdoor VOCs and indoor sources. For most compounds, the ratio is close to one, indicating a strong influence of outdoor environmental pollution on in indoor VOCs. High ratios with significant differences between indoor and outdoor concentrations indicate a strong source of indoor VOCs. For, e.g., high ratios were found for terpenes, indicating an indoor source, which is likely to be room deodorizers, furniture polisher, or household cleaners .
Formaldehyde is a colorless, flammable chemical that has widespread use and is abundant in substances all around us. It is used in the production of industrial resins, building material, and several household products including particleboard, fiberboard, glues and adhesives, and certain insulations. It is also used in consumer products as a biocide and preservative and in medical settings as a disinfectant and preservative. It is a ubiquitous chemical that is found both indoors and outdoors. Exposure to the general population is primarily due to automobile exhaust, cooking, heating, cigarette smoke, and from gases released from construction and home furnishing materials. Based on animal and epidemiological studies, formaldehyde was classified as a group I carcinogen to humans by the IARC . Several studies in rats have tested the effect of exposure of formaldehyde in animal models. Chronic exposure in rats by inhalation or through drinking water resulted in squamous cell carcinoma of the nasal cavity. In human epidemiological studies, both cohort and case–control, exposure to formaldehyde was shown to result in increased risk for nasopharyngeal cancers, sinonasal cancers, and lymphohematopoietic cancer (leukemia, myeloid leukemia, and acute myeloid leukemia) [81–83]. An increase in peak exposure also increased the risk for cancers.
Formaldehyde is an essential metabolic intermediate in all living cells and is produced by most organisms. It is metabolized by glutathione-dependent enzymes to formic acid or carbon dioxide and eliminated from the body. Excess formaldehyde that does not get metabolized reacts with protein and DNA to form protein–DNA crosslinks , DNA–DNA crosslinks, DNA strand breaks [85–87], and causes cytogenetic effects (such as chromosomal aberrations, sister chromatid exchange) [88–90]. Formaldehyde is believed to act through its ability to bind DNA, induce mutation, and affect expression of genes involved in various cellular pathways including cell cycle regulation, apoptosis, inflammation, nucleic acid metabolism, and DNA repair, although the exact mechanism of action for formaldehyde induced tumorigenesis has not explained yet.
Benzene is a widespread environmental contaminant in the air and groundwater, originating from industrial sources, cigarette smoke, gasoline, and automobile emissions. In rodents, benzene causes a range of neoplasms, including lymphomas and tumors of epithelial origin . The toxic effects of benzene are dependent on its metabolism by the cytochrome P450 enzyme system. Studies have identified CYP2E1 as the primary P450 isozyme responsible for benzene metabolism at low concentrations, whereas CYP2B1 is involved at higher concentrations . Studies using microsomal preparations from human, mouse, and rat indicate that CYP2E1 is the P450 isozyme primarily responsible for benzene metabolism in lung and in liver. CYP2B isozymes have little involvement in benzene metabolism by either lung or liver. Benzene is known to cause leukemia, particularly acute non-lymphocytic leukemia, and perhaps other hematologic neoplasms and disorders in human [93, 94]. Even though there is scientific agreement that benzene causes leukemia, particularly acute nonlymphocytic leukemia (ANLL), controversy still exists with regard to the level of risk at low exposures as well as the potential association with other hematologic neoplasms. In a recent meta-analysis, Vlaanderen et al.  claimed to show evidence for associations between occupational benzene exposure and risks of multiple myeloma, acute lymphocytic leukemia, and chronic lymphocytic leukemia. An increased risk of breast cancer among women exposed to benzene has also been suggested after analyzing the breast cancer risk in a cohort of 1,002 women exposed to benzene in a shoe factory in Florence, Italy, where an excess of leukemia in men was reported 
Workers with prolonged exposure to pesticides in the agricultural industry and landscaping professions are at a higher risk for cancer . While approximately 20 pesticides have been classified as animal carcinogens, only a few pesticides are established as human carcinogens, and a few more are known to act as tumor promoters . Some of the cancers most commonly associated with pesticide exposure include non-Hodgkin's lymphoma (NHL), leukemia, as well as brain, breast, kidney, pancreatic, prostate and stomach cancers [99–102]. Neonatal and childhood exposure to pesticides is associated with leukemia and renal cancers .
Organochlorines, creosote, and sulfallate are classes of arsenic compounds, insecticides, and pesticides that are classified as animal carcinogens . Exposure to organophosphorus insecticides has been implicated in non-Hodgkin's lymphoma, leukemia and in the risk of brain tumor development in children, especially when coupled with existing genetic variations. Phenoxy acid herbicides have been associated with soft tissue sarcoma (STS); organochlorine insecticides with STS, NHL, and leukemia; and triazine herbicides with ovarian cancer . Organochlorines dichlorodiphenyltrichloroethane (DDT), chlordane, and lindane are identified as tumor promoters .
Legislation has been made to curb certain pesticide usage due to the strong association between pesticide exposure and cancer risk . In some cases, pesticide usage is restricted for uses such as landscaping or golf course maintenance . Many countries have removed known animal carcinogen pesticides from the market entirely; however, a portion of these products are still exported to developing countries. Further studies are needed to establish and investigate the correlation between pesticide exposure and cancer incidences, and it is crucial to promote public education on the proper handling of these hazardous substances.
The body requires some metals in minute quantities but large doses of some heavy metals have been implicated in various health problems and cancer. When these metals are consumed in large quantities or exposed to the body in large amounts, they can accumulate in the body and cause toxic effects. More specifically, some metals have deleterious effects on the cell by inducing DNA damage and introducing mutations. Metals such as chromium, nickel, and arsenic are known to have carcinogenic effects [103, 104]. Experimental and epidemiological data have linked exposure to these chemicals as having a role in lung and nasal cancers, more specifically in the industrial setting. Arsenic can be found in both organic and inorganic forms. Organic forms are less harmful and have fewer implications in cancer while the inorganic forms found in the manufacturing and industrial settings are thought to be associated with cancer. Even though legislation has limited workplace exposure to arsenic, some workers can still be exposed to factories that use arsenic as a treatment for lumber or use arsenic compounds in pesticides and even glass production factories [105, 106]. Research has also demonstrated that exposure to arsenic from drinking water can increase the risk for cancer. The current standard set by the United States Environmental Protection Agency (USEPA) in drinking water is 10 ppm . A number of populations are still receiving the drinking water supply with high levels of arsenic. Studies show that at least 350,000 people drink water with considerably higher arsenic levels. Therefore, the cancer risk associated with arsenic in the drinking water can be comparable to the risks associated with tobacco smoke and radon exposure.
Humans are exposed to mycotoxins via ingestion, contact, and inhalation. Potential risks of diseases from the mycotoxin exposure range from akakabio-byo to stachybotryotoxicosis and cancer . The known molecular basis of mycotoxin toxicology include the gamut of 23 compounds, from aflatoxins (AFs) to zearalenone, ochratoxin A, and deoxynivalenol.
Mycotoxins are well known in the scientific community, although they have a low profile in the general population. This contrasts with thousands of deaths from mycotoxins that occur, even now, in the technologically less-developed countries (e.g., Indonesia and Africa). Mycotoxins are more toxic than pesticides. An incongruous situation occurs in United States where mycotoxins from “moldy homes” are considered to be a significant problem, although there is a general debate about its seriousness .
Ergotism is one of the oldest recognized mycotoxicosis, although mycotoxin science only commenced in the 1960s with the discovery of AFs in turkey feed. Since then AFs have become recognized as ubiquitous contaminants of the human food supply throughout the economically developing world. The adverse toxicological consequences of these compounds in populations are quite varied because of a wide range of exposures leading to acute effects, including rapid death, and chronic outcomes such as hepatocellular carcinoma.
Chemically, aflatoxins are highly substituted coumarins containing a fused dihydrofurofuran moiety . Four aflatoxins occur naturally: B1, B2, G1, and G2. Members of the blue fluorescent series are characterized by fusion of a cyclopentenone ring to the lactone ring of the coumarin moiety, whereas the green fluorescent toxins contain a fused lactone ring. Aflatoxins B1 and B2 (AFB1 and AFB2) were so named because of their strong blue fluorescence in ultraviolet light, whereas aflatoxins G1 and G2 (AFG1 and AFG2) fluoresce greenish yellow.
The carcinogenic potency of AFB1 has been well established in many species of animals, including rodents, nonhuman primates, and fish. The data on aflatoxin and human liver cancer exemplify the importance of these elements and provide a model for the design of future studies for risk assessment of exposure to other environmental agents . Widespread concern about the potential deleterious effects of aflatoxins in humans and animals as well as possible transfer of residues into edible animal tissues and milk has led to regulatory actions governing U.S. interstate as well as international commerce involving food and feed commodities that may be contaminated with aflatoxins.
The environment plays a significant role in causing various human cancers. Apart from the above-described contributors of environmental carcinogenesis, other environmental factors such as asbestos and exposure to radiation also pose significant risk for cancer. The environmental agents that are recognized as carcinogens show variable levels of cancer-causing potential. The cancer-causing potential of a carcinogen is contingent upon the length of exposure, its intensity, and the individual genetic makeup. Exposure to chemicals, radiation, and infections is responsible for a number of cancers while lifestyle and personal habits such as smoking and alcohol consumption pose a major impact in the onset of cancer and recovery from other health conditions. Tobacco is considered a global epidemic in causing health hazards and the American Cancer Society estimates that smoking is responsible for at least 30 % of cancer-related deaths in the United States alone. Occupational exposure is a serious concern in the cause of cancer. Apart from the regulatory agencies, both the employer and the employee should meticulously take proper precautions and seek novel insights in the issue of health hazards associated with occupational exposure.
Understanding the cellular and biochemical perturbations caused by various environmental agents that are detrimental to human health by posing the risk of causing cancer, is crucial and beneficial. Recent advances in science and technology have provided the tools to the changes taking place at molecular level. This has enabled scientists and physicians to assess altered pathways in cancer cells and further develop tools to delineate the underlying mechanisms of carcinogenesis. The actual mechanisms and cellular biochemical processes of environmental disposition in causing various cancers are not fully understood. The potential mechanisms proposed for at least some of the carcinogens include alterations in signaling pathways associated with apoptosis and cell cycle. Formation of DNA adducts leading to mutation in p53 and KRAS and other potential markers are well established in environmental carcinogenesis, while some compounds require bioactivition through CYP enzymes to exert carcinogenic activity (Figs. 1 and 2).
Due to the impervious complexity of the disease, and differential response of patients to therapy, it is imperative for the scientific community to harness new insights and strategies for the prevention of this devastating disease. Even though many environmental factors potentially impact cancer incidence and prognosis, more than 30 % of these diseases could be prevented, mainly by avoiding exposure (direct or indirect) to tobacco, consuming a healthy diet, maintaining physical activity, and preventing infections that may cause cancer.
Authors greatly appreciate the financial and technical support provided by the MD Anderson Cancer Center Orlando's Cancer Research Institute.
Conflicts of interest